RESEARCH STRATEGY/PROJECT SUMMARY/ABSTRACT This Administrative Supplement to our Small Business Innovation Research Phase II project will take advantage of new advances in liquid handling instrumentation to augment our efforts in developing high-content (HCS) and high-throughput screening (HTS) systems for the discovery of novel therapeutics and/or modulating systems for use in the treatment of neurodegenerative disorders including Gaucher, Krabbe, Fabry, Tay-Sachs, Sandhoff and other lysosomal storage diseases as well as Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Type 2 diabetes, Lowe syndrome, Huntington's disease and their allied medical conditions. The ability to accurately plate out equal numbers of live cells into 96-well or 384-well tissue culture plates for these HTS and HCS applications is paramount to obtaining consistent and reliable results. Robust and reliable methods for the manipulation of human cell lines by passaging, plating and labeling are required to enable consistent, reproducible screens to be performed. With the help of this supplement, we intend to develop procedures and processes to maximize the level of consistency of cell plating and analysis, to ensure that the assays which we are running on a routine basis remain consistent across multiple runs and to apply these methods in the screening of large libraries of compounds. These procedures involve a variety of fully or semi-automated steps, using high-quality commercially available liquid handling and dispensing technologies. Therefore, we propose the purchase of a Molecular BioProducts/Thermo- Fisher Versette? automated liquid handling instrument. The Versette? has replaced the Thermo- Electron Multidrop as the state-of-the-art cell dispensing technology at Thermo-Fisher research labs and at HCS screening facilities worldwide [1-5]. The Versette will be integrated with our existing Thermo- Fisher Countess II FL Cell Counter and CellInsight? CX5 High Content Screening (HCS) Platforms to provide absolute cell counts, measure viability, determine whether cells to be plated from suspension consist of single cells [6] and perform the HCS screening and analysis of potential drug candidates. The ultimate goal and the overall impact of this project is to provide an understanding of the dynamic processes that occur in intracellular enzyme and protein trafficking defects in human disease and to obtain information that will provide a pathway to the discovery of more efficacious treatment options. The use of these systems for screening libraries of potential drug candidates for their ability to modulate enzyme function, trafficking and intracellular localization will identify new small molecule therapeutic leads based on these parameters. These systems will be used in our CRO activities as well as for a variety of significant cell biology, biochemical, diagnostic and medical applications with our collaborators in both academia and industry.